EP1567869B1 - Verfahren zum screening für verbindungen mit sedativer oder anxiolytischer potenz - Google Patents

Verfahren zum screening für verbindungen mit sedativer oder anxiolytischer potenz Download PDF

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Publication number
EP1567869B1
EP1567869B1 EP03796034A EP03796034A EP1567869B1 EP 1567869 B1 EP1567869 B1 EP 1567869B1 EP 03796034 A EP03796034 A EP 03796034A EP 03796034 A EP03796034 A EP 03796034A EP 1567869 B1 EP1567869 B1 EP 1567869B1
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Prior art keywords
compound
hpa axis
sedative
screening
anxiolytica
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French (fr)
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EP1567869A1 (de
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Jens Damsgaard NeuroSearch A/S Mikkelsen
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NTG Nordic Transport Group AS
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Neurosearch AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
    • G01N33/9406—Neurotransmitters
    • G01N33/9426—GABA, i.e. gamma-amino-butyrate

Definitions

  • the present invention relates to a method for screening a chemical compound for its potential as a sedative or anxiolytica.
  • GABA is the major inhibitory neurotransmitter in the mammalian brain and the GABA A receptor is the site of action of benzodiazepines. Multiple isoforms of GABA A receptor exist; each receptor comprises a pentameric complex formed by co-assembly of subunits selected from 16 genes ( ⁇ 1-6 , ⁇ 1-3 , ⁇ 1-3 , ⁇ , ⁇ , ⁇ , and ⁇ ) creating a chloride ion-channel.
  • the most abundant GABA A receptor in the mammalian brain comprises ⁇ , ⁇ , and ⁇ subunits, and the classical anxiolytic benzodiazepines bind to these receptors if they contain ⁇ 1,2,3 or 5 and ⁇ 2 subunits. Because the subtypes are differently expressed in the brain as well as in other organs and because different subtypes are considered to be involved in different function, subtype specific compounds have been developed both with agonistic, antagonistic and inverse agonistic potentials.
  • An example of such a subtype specific compound is the non-anxiolytic imidazopyridine zolpidem, which is highly selective for ⁇ 1 containing GABA A receptors and is used as a short acting sedative in humans.
  • ⁇ 2 , ⁇ 3 , and ⁇ 5 benzodiazepines sites are considered to be involved in anxiolytic properties and similar attempts have been made develop specific compounds for these sites.
  • Such an example is the compound L-838,417, which is a selective ⁇ 2 , ⁇ 3 , and ⁇ 5 agonist [ McKernan et al., Nat. Neurosci. 2000 June; 3(6); 587-92 ].
  • NCE new chemical entities
  • behavioural testing is essential to determine pharmacokinetic and other ADME properties of the NCE.
  • efficacy in terms of hypnotic, sedative, anxiolytic, muscle relaxant, and anticonvulsive properties.
  • Behavioural analyses in animals involve a number of so-called anxiety models, which detect the subjects' capability to take risks. The major problem with these models is that they are only partly predictive to assess a full behavioural response to a NCE with in vitro effect on the GABA A receptor. There exists no in vivo prediction of alpha selectivity. Furthermore, because some of these compounds are sedative, it is hard to determine if their lack of action is specific or linked to its sedative properties. A method that activates systems in the brain relevant for the action of subtype specificity of NCE is therefore badly needed.
  • the hypothalamo-pituitary-adrenal (HPA) axis consists of the hypothalamic corticotrophin releasing factor (CRF) neurons in the medial parvocellular nuclei of the paraventricular nucleus (PVN), the corticotrophs of the anterior pituitary, and the steroid-producing cells in the adrenal cortex.
  • the HPA axis drives the release of circulating corticosteroids in the blood, and is thus a central component of the stress response.
  • the HPA axis is under negative feedback, as increasing concentrations of plasma corticosteroids will inhibit the activity of the HPA axis via specific receptors for glucocorticosteroids.
  • the HPA axis is under influence by other centers in the brain, and thereby it is activated in response to anxiety and fear. Pharmacological intervention can affect either directly on stress-related pathways, on the CRF neurons, or peripherally to affect the inhibitory feedback on the axis.
  • Diazepam has been shown to slightly stimulate the HPA axis at the level of the hypothalamic corticotrophin releasing factor (CRF) neurons.
  • CRF corticotrophin releasing factor
  • WO 01/05222 and WO 02/40700 relate to transgenic mice deficient in corticotrophin releasing factor receptor 2.
  • WO 00/44752 relates to triazolo-pyridazine derivatives as ligands for GABA receptors.
  • the invention relates to a method for screening a GABA A receptor modulator for its potential as a sedative or anxiolytica.
  • the invention provides a method for screening a GABA A receptor modulator for its potential as a sedative or anxiolytica, which method comprises the following steps:
  • the test animal is a non-human animal, such as a mammal.
  • the test animal is a rodent, such as a mouse or a rat.
  • the test animal is a non-mammalian vertebrate, such as a reptile, bird or fish.
  • the route of exposure of the compound is intraperitoneal (i.p.), intraveneous (i.v.), peroral (p.o.) or subcutaneous (s.c.).
  • the measurement of the activity of the HPA axis is performed by measuring, in a blood sample from the test animal after administration, the level of plasma corticosterone and/or ACTH.
  • the method for screening comprises the further step of: c1) selecting the compound as a sedative drug candidate if the compound stimulates the HPA axis.
  • the stimulation of the HPA axis is at least a 2-fold increase, preferably at least a 3-fold increase, in corticosterone and/or ACTH over vehicle within the first two hours of administration.
  • the method for screening comprises the further step of: c2) selecting the compound as an anxiolytica drug candidate if the compound has no effect on the HPA axis.
  • no effect on the HPA axis is less than a 50 percent increase, preferably less than a 25 percent increase, in corticosterone and/or ACTH over vehicle within the first two hours of administration.
  • HPA axis hyperthalamus-pituitary-adrenal axis
  • a good measure of the activity of the HPA axis is a measure of those hormones that are released in response to the activation, i.e. the adrenocorticotrophic hormone (ACTH) and glucocorticoids (such as corticosterone or cortisol).
  • ACTH adrenocorticotrophic hormone
  • glucocorticoids such as corticosterone or cortisol
  • GABA A receptor modulator as identified by the method according to the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • compositions comprising the GABA A receptor modulator of the invention, or a pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers therefor, and, optionally, other therapeutic and/or prophylactic ingredients, know and used in the art.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • the pharmaceutical composition may be administered by any convenient route which suit the desired therapy.
  • Preferred routes of administration include oral administration, in particular in tablet, in capsule, in dragé, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection.
  • the pharmaceutical composition may be prepared by the skilled person using standard and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.
  • mice Twenty-27 g. were purchased from M ⁇ llegaarden (Denmark). The animals were received at the animal facility, and housed 5 per cage under 12:12 light: dark cycle, humidity and temperature controlled room for at least 7 days before the experiment. Food and water were available ad libitum. All procedures were conducted in accordance with the Danish National Guide for Care and Use of Laboratory animals. Zolpidem was purchased from Tocris Ltd (Bristol, UK) and L-838,417 synthesised according to WO 98/04559 and was injected in a volume of 10 ml/kg and dissolved in 5% Chremophor.
  • mice were administered (i.p.) at doses 0,025, 1,25, 2.5, 12.5 and 25 mg/kg.
  • the mice were returned to their home cages and sacrificed by decapitation 60 minutes after drug administration and trunk blood was collected in centrifuge tubes containing 2 mg EDTA. Plasma aliquots were stored at -20°C until hormone levels were determined.
  • Plasma corticosterone was measured directly without prior extraction by a commercially [ 125 I] corticosterone radioimmunoassay kit from Amersham. The experiment was performed twice. The data were analysed by a two-way analysis of variance (ANOVA) followed by the Dunn's test. All data are represented as group means and the standard error of means (SEM).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (5)

  1. Verfahren zum Screening eines GABAA-Rezeptor-Modulators auf sein Potential als Sedativum oder Anxiolytikum, wobei das Verfahren die folgenden Schritte umfasst:
    a) Einwirkenlassen der Verbindung auf ein nichtmenschliches Versuchstier, wobei die Verbindung zu verabreichen ist; und
    b) Messen der Wirkung der Verbindung auf die Aktivität der HPA-Achse; und
    c) Auswählen der Verbindung als Arzneistoffkandidat für ein Sedativum, wenn die Verbindung die HPA-Achse stimuliert, oder
    Auswählen der Verbindung als Arzneistoffkandidat für ein Anxiolytikum, wenn die Verbindung keine Wirkung auf die HPA-Achse hat.
  2. Verfahren nach Anspruch 1, wobei das Versuchstier eine Maus oder eine Ratte ist.
  3. Verfahren nach Anspruch 2, wobei die Messung der Aktivität der HPA-Achse durchgeführt wird, indem nach der Verabreichung der Plasmaspiegel von Corticosteron und/oder ACTH in einer Blutprobe von dem Versuchstier gemessen wird.
  4. Verfahren nach einem der Ansprüche 1 bis 3, umfassend den Schritt:
    c1) Auswählen der Verbindung als ein Arzneistoffkandidat für ein Sedativum, wenn die Verbindung die HPA-Achse stimuliert.
  5. Verfahren nach einem der Ansprüche 1 bis 3, umfassend den Schritt:
    c2) Auswählen der Verbindung als Arzneistoffkandidat für ein Anxiolytikum, wenn die Verbindung keine Wirkung auf die HPA-Achse hat.
EP03796034A 2002-11-28 2003-11-21 Verfahren zum screening für verbindungen mit sedativer oder anxiolytischer potenz Expired - Lifetime EP1567869B1 (de)

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DK200201840 2002-11-28
DKPA200201840 2002-11-28
PCT/EP2003/050860 WO2004048980A1 (en) 2002-11-28 2003-11-21 Method for screening for compounds as potential sedatives or anxiolytics

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EP1567869B1 true EP1567869B1 (de) 2007-08-22

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US (1) US20060013770A1 (de)
EP (1) EP1567869B1 (de)
JP (1) JP4426461B2 (de)
AT (1) ATE371193T1 (de)
AU (1) AU2003298302A1 (de)
DE (1) DE60315876T2 (de)
WO (1) WO2004048980A1 (de)

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JP5183808B2 (ja) * 2008-08-29 2013-04-17 コンサート ファーマシューティカルズ インコーポレイテッド 置換トリアゾロ−ピリダジン誘導体

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US6500828B1 (en) * 1999-01-27 2002-12-31 Merck Sharp & Dohme Ltd. Triazolo-pyridazine derivatives as ligands for gaba receptors
US7674463B1 (en) * 1999-07-15 2010-03-09 Research Development Foundation Method of inhibiting angiogenesis by administration of a corticotropin releasing factor receptor 2 agonist
AU780829B2 (en) * 1999-07-15 2005-04-21 Research Development Foundation Corticotropin releasing factor receptor 2 deficient mice and uses thereof

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ATE371193T1 (de) 2007-09-15
WO2004048980A1 (en) 2004-06-10
EP1567869A1 (de) 2005-08-31
JP2006513405A (ja) 2006-04-20
US20060013770A1 (en) 2006-01-19
DE60315876T2 (de) 2008-05-21
DE60315876D1 (de) 2007-10-04
AU2003298302A1 (en) 2004-06-18
JP4426461B2 (ja) 2010-03-03

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